The long-term objective of this proposal is to contribute to the understanding of the initial development of the cerebral cortex. Specifically, we propose to study the role of human Cajal-Retzius (C-R) cells and layer I during early development. The overriding hypothesis to be tested is that the C-R cells are a diverse population of cells and that species- related differences in this diversity accounts for the fate of these cells during development. Cajal-Retzius cells are the main type of cell in the initial layer I (the preplate). By secreting the glycoprotein, reelin, C-R cells have been postulated to control the inside-out migration of cortical neurons and thus to play a fundamental morphogenic role in corticogenesis. The disruption of this process has been implicated in various neurodevelopmental disorders resulting in mental retardation, ectopias and epilepsy. In order to understand and ultimately prevent these pediatric disorders, there is a need to gain an appreciation of the mechanisms underlying normal brain development. Recent studies employing new markers of early cortical neurons reveal a cellular composition of the human preplate that is much more complex than the prevailing classical model. In this application, we propose 3 specific aims to address some of the most controversial and pressing issues related to C-R cells in human cortical development. We would like to know the answers to the following questions: (1) Do all C-R cells belong to a single unique class of cells or should they be classified instead into different subtypes on the basis of their antigenic phenotype, survival rate and transmitter receptor properties? (2) Are C-R cells generated at different times and from different places? (3) How do species- specific differences relate to functional properties, the survival and possible new roles of C-R cells in humans? Having available to us a well-characterized collection of human brains that spans the intrauterine period of development, we are in a uniquely favorable position to answer these questions. Normal development of the cerebral cortex is essential for proper functioning of the adult central nervous system. Data generated through this research will advance our understanding of normal brain development, and point to possible mechanisms that contribute to congenital brain malformations. In addition, our findings will establish a prerequisite set of baseline data for proper diagnosis and treatment of pediatric disorders of the CNS.